Hyperfunction of Muscarinic Receptor Maintains Long-Term Memory in 5-HT4 Receptor Knock-Out Mice

Patients suffering from dementia of Alzheimer''s type express less serotonin 4 receptors (5-HTR₄), but whether an absence of these receptors modifies learning and memory is unexplored. In the spatial version of the Morris water maze, we show that 5-HTR₄ knock-out (KO) and wild-type (WT) mice performed similarly for spatial learning, short- and long-term retention. Since 5-HTR₄ control mnesic abilities, we tested whether cholinergic system had circumvented the absence of 5-HTR₄. Inactivating muscarinic receptor with scopolamine, at an ineffective dose (0.8 mg/kg) to alter memory in WT mice, decreased long-term but not short-term memory of 5-HTR₄ KO mice. Other changes included decreases in the activity of choline acetyltransferase (ChAT), the required enzyme for acetylcholine synthesis, in the septum and the dorsal hippocampus in 5-HTR₄ KO under baseline conditions. Training- and scopolamine-induced increase and decrease, respectively in ChAT activity in the septum in WT mice were not detected in the 5-HTR₄ KO animals. Findings suggest that adaptive changes in cholinergic systems may circumvent the absence of 5-HTR₄ to maintain long-term memory under baseline conditions. In contrast, despite adaptive mechanisms, the absence of 5-HTR₄ aggravates scopolamine-induced memory impairments. The mechanisms whereby 5-HTR₄ mediate a tonic influence on ChAT activity and muscarinic receptors remain to be determined.